Mounting studies have identified that a combination of biological and mechanical factors disrupts the synthesis and degradation balance of chondrocytes, ECM, and subchondral bone, causing cartilage degeneration, fibrosis, and subchondral callus.(Xia et al., 2014) (Lieberthal et al., 2015) (Carballo et al., 2017) (Y. Wang et al., 2017) (Trachana et al., 2019) Mechanical stimulation leads to metabolic changes, which are characterized by the release of inflammatory mediators and MMPs and the degradation of ECM.(Mehana et al., 2019) (Yang et al., 2020) (Philpott et al., 2017) (Rahmati et al., 2017) Under normal circumstances, anabolism and catabolism of ECM are in a dynamic equilibrium, which is essential for a healthy joint.(Rahmati et al., 2017) Once the balance is disrupted, it leads to irreparable joint cartilage damage and OA symptoms. Alleviating the inflammatory mediators and ECM degradation is a key player in the prevention versus treatment of OA. Despite some breakthroughs made in illuminating the pathogenesis of OA, there are no disease-modifying drugs with evidently validated therapeutic effects to modify the progression of OA at present.(Quicke et al., 2022) (Jiang, 2022) (Lieberthal et al., 2015)
Natural products could treat various human diseases, including OA, after their widespread use, half of which are likely extracted from plants.(Zhou et al., 2019) (Wu et al., 2019) (Z. Wang et al., 2017) (Y. Hu et al., 2019) (H. Hu et al., 2018) AKBA, a pharmacologically active pentacyclic triterpenes compound from Boswellia serrate extract, has been reported previously to alleviate host inflammatory response, mitigating inflammation-induced damage to diabetes, bronchial and nervous tissue.(Meka et al., 2017) (Takada et al., 2006) (Ding et al., 2016) (Sayed et al., 2018) In addition, it has been reported that AKBA has anti-osteogenic inhibition, anti-ulcer, anti-asthma, anti-oxidative stress, anti-tumor, and lipid regulatory effects.(Tambe et al., 2019) (Rajabian et al., 2020) (Li et al., 2018) AKBA inhibited inflammation through NF-κB-regulated gene expression. We concluded that AKBA reversed the imbalance of LPS-induced inflammation and ECM metabolism by inhibiting the NF-κB pathway. Additionally, we demonstrated that AKBA intervention alleviated the progress of OA in a rat Hulth-Telhag OA model for the first time.
Several studies have reported that the NF-κB signaling pathway plays an important role in the pathophysiological process of OA and is activated by the inflammation of OA, as such, the upstream regulators, co-factors, and downstream effectors of NF-κB have become promising targets of OA and rheumatoid arthritis therapies.(Lepetsos et al., 2019) (Napetschnig & Wu, 2013) (Jimi et al., 2019) Based on current studies, NF-κB plays a vital part in inducing various inflammatory-related factors, including IL-1β, IL-6, TNF-α, and MMP proteins, which can stimulate chondrocyte catabolism.(Herrero-Beaumont et al., 2019) (Catrysse & van Loo, 2017) (Khan et al., 2017) NF-κB is also related to ECM degradation. As the two most abundant components in the ECM, aggrecan and col II are degraded by MMPs, whose increased expression is regulated by NF-κB.(Hussain et al., 2018) (Luo et al., 2019) Furthermore, NF-κB can phosphorylate and degrade IκB protein when chondrocytes are stimulated by various stimuli, causing the transport of NF-κB p65 to the nucleus, where p65 facilitates OA-related gene and protein expression. Our study suggested that AKBA treatment inhibited the overexpression of IL-1β, IL-6, and TNF-α using Western blot and qRT-PCR. Further, AKBA treatment reversed the degradation of aggrecan and col II and the upregulation of MMPs. The results also suggested that AKBA treatment could inhibit nuclear translocation of p-p65 by Western blot and IF analyses. Taken together, these results showed that AKBA treatment plays a positive role in anti-inflammation and ECM degradation by inactivating the NF-κB signaling pathway (Fig. 6).
3-O-C12-HSL, one of the AHLs frequently identified in extracts of respiratory secretions from cystic fibrosis patients infected with Pseudomonas aeruginosa and Burkholderia cepacia complex species and acts as an activator of NF-kB, was used to verify the role of the NF-kB pathway.(Henke & Bassler, 2004) (Chambers et al., 2005) (Smith et al., 2001) IF assay indicated that AKBA treatment depressed nuclear translocation of p65 after LPS-induced cytoplasmic localization. However, 3-O-C12-HSL treatment reversed the effects of AKBA on the inhibition of p65 in chondrocytes. Overall, our results demonstrated that AKBA intervention restrained LPS-induced inflammation and ECM degradation via suppression of the NF-κB signaling pathway.